Novel 17-[(methylthio)methoxy] yohimbanes



United States Patent 3,37 3,166 NOVEL 17-[(lVIETI-IYLTHIO)METHOXY] YOHMBANES Jay Donald Albright and Leon Goldman, Nanuet, N.Y., assignors toAmerican Cyanamid Company, Stamford, Conn, a corporation of Maine NoDrawing. Continuation-impart of application Ser. No. 556,584, June 10,1966. This application Euiy 7, 1%7, Ser. No. 651,673

19 Claims. (Cl. 260-287) ABSTRACT OF THE DISCLQSURE This disclosuredescribes compounds of the class of ring-E substituted 17[ (methylthio)methoxy] yohimbanes useful as central nervous system depressan CROSSREFERENCE TO RELATED APPLICATION This application is acontinuation-in-part of our copending application Ser. No. 556,584,filed June 10, 1966, now abandoned.

BRIEF SUMMARY OF THE INVENTION This invention relates to new organiccompounds and, more particularly, is concerned with novel17-[(methylthio)rnethoxy]yohimbanes which may be represented by thefollowing general formula:

O CHZSCHg wherein R is hydrogen or lower carboalkoxy and R is hydrogenor lower carboalkoxy, with the proviso that R; and R cannot be the same.Suitable lower cwboalkoxy groups contemplated by the present inventionare those having from 2 to 6 carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION wherein R and R are as hereinabovedefined, with dimethyl sulfoxide and a carboxylic acid anhydride. Thesestarting materials for the preparation of the novel compounds of thepresent invention are derivatives of yohimbane belonging to the normal,pseudo, allo and epial- 10 series depending upon the cis or trans fusionof the D and E rings and the configuration at the 3-position. Thepreparation of these appropriately substituted 17-hydroxy yohimbealkaloid starting materials may be found in the following references:Hesse, Indolalkaloide in Tabellen, 76-78, SpringerVerlag, Berlin (1964);Godtfredsen et al., Acta. Chem. Scand, 11, 1013 (1957); Janot et al.,Bull. Soc. Chim. France, 637 (1961); Albright et al., J. Org. Chem, 28,38 (1963). Typical l'i-hydroxy yohimbe alkaloid starting materials whichmay be employed to prepare the novel 17-[(methylthio)methoxy] yohimbanesof the present invention are, for example, yo-himbine, fi-yohimbine,tz-yohirnbine, methyl 3-epi-l7fihydroxyyohimban-16tx-carboxylate, methyl3-epi-17a-hydroxyyohirnban-llx-carboxylate, methyl3-epi-17a-hydroxyyohirnban-l6/3-carboxylate, methyl3-epi-l7a-hydroxyalloyohimban-16,8-carboxylate, methyll7fi-hydroxyalloyohirnban-16,6-carboxylate, methyl 17oz-hYdfOXYYO-himban-18tz-carboxylate and methyl 17,8-hydroxyyohimban-l8a-carboxyalte.

We have found that when yohirnbe alkaloids containing a l7-hydroxy groupare allowed to react with dimethyl sulfoxide and a carboxylic acidanhydride, in competition with oxidation of the 17-hydroxy function to aketone, the novel products of the present invention containing al7-(methylthio)methoxy group are formed. The reaction is carried out bycontacting the 17-hydroxy yohimbe alkaloid with dimethyl sulfoxide and a120 mole excess of a carboxylic acid anhydride such as acetic anhydn'de,benzoic anhydride, propionic anhydride, and the like, at 0 C. to 60 C.Preferably, the reaction mixture is allowed to stand at 20 C. to 30 C.,protected from moisture, for sufiicient time to insure completion of thereaction. The reaction time is not critical, however a period of 6 to 60hours is generally satisfactory. If desired, an inert solvent such asbenzene, toluene, chloroform, dichloromethane, N,N-dimethylformarnide,acetic acid, dioxane or tetrahyclrofuran may be employed as diluent. Theproduct may be recovered by pouring the reaction mixture onto ice and,after standing, then made basic in the cold with a base such as ammoniumhydroxide or aqueous sodium hydroxide. The mixture is then extractedwith a suitable Water immiscible organic solvent such :as chloroform,dichloromethane, and the like. Concentration of the organic extractsthen gives the crude product which is purified by crystallization orchromatography to give the l7-(methylthio)methoxy derivative.

The novel compounds of the present invention are valuable centralnervous system depressants of low toxicity and were shown to possess CNSdepressant activity as determined by animal experiments as follows. Thecompounds studied were administered intraperitoneally in a 2% starchvehicle to groups of six mice at three or more graded dose levels. At15-minute and 30-minute intervals after treatment, each animal wasplaced on the midpoint of a horizontal steel rod (1.55 cm. in diameterand about 6 dm. in length), positioned 45.7 cm. above the surface of thetable, and forced to walk toward a platform at either end of the rod.The criterion of inability to perform this act was consistent slippingto the side or falling off the rod. Eifective doses for reducedrod-walking ability (RWD were calculated or approximated from the data,and the time of peak effect was estimated from the data. One-half of theRWD dose Was given intraperitoneally to each mouse in groups of five. Atthe time of peak effect, as determined above, each group of mice Was putinto the actophotometer for a period of five minutes and the motoractivity counts were recorded and compared to controls. Those compoundsthat appeared to reduce motor activity by 50% were administered toadditional groups of five mice at graded doses and tested similarly. Thedose (MDD that caused a 50% reduction in motor activity was estimated.In a representative operation, and merely by way of illustration, methyl17,8-[(methylthio)rnethoxy]yohimbanlrm-carboxylate was shown to induceataxia (RWD at a dose of 98 mg./kg. of body weight and to reducelocomotor activity (MDD at a dose of 17 rug/kg. of body weight.

The novel compounds of the present invention are also valuableanti-inflammatory agents and were shown to possess anti-inflammatoryactivity as determined by animal experiments as follows. In arepresentative operation, suppression of carrageenin-induced foot edemaand U.V.-induced ear erythema was obtained in rats when methyl17w[methylthio)methoxy]yohimban 16oz carboxylate was administered orallyat a dosage of 100 and 350 nag/kg. of body weight, respectively. Also,and merely by way of further illustration, temperature suppression ofanti-yeast-induced pyresis was obtained in rats when methyl17a-[(methylthio)methoxyyohimban- 16a-carboxylate was administeredorally at a dosage of 7.4 rug/kg. of body weight.

The present invention also embraces the useful nontoxic pharmaceuticallyacceptable acid-addition salts of these novel componnds..Typicalacid-addition salts are the hydrochlorides, hydrobromides, sulfates,citrates, tartrates, succinates, and the like. Although the novelcompounds of the present invention may be used as such, they are morepreferably administered in the form of their non-toxic acid-additionsalts which may be readily prepared by treatment with one or twoequivalents of an acid such as hydrochloric, sulfuric, phosphoric,citric, etc., in a suitable solvent.

The invention will be described in greater detail in conjunction withthe following specific examples.

Example 1 PREPARATION OF METHYL 17d-[ (METHYLTHIOMETHOXY1YOHIMBAN-lfSa-CARBOXYLATE To a mixture of 886 g. of yohimbineand 7.55 l. of dry dimethyl sulfoxide is added 5.05 l. of aceticanhydri-de. The mixture is stirred at room temperature for 18 hours. Themixture is diluted with 16.8 1. of ethanol, stirred for one hour anddiluted with 4.2 l. of water. Concentrated ammonium hydroxide (11 l.) isadded while maintaining the temperature at 30 C. by cooling and themixture is then diluted with 16.8 1. of water. Filtration gives a solidwhich is washed with water and dried. The solid is slurried with 4 l. ofethanol and filtered and the filtrate is concentrated under reducedpressure to give a dark colored gum. The gum is dissolved inchloroforrn:acetonezethanol (6:3:1) and filtered through syntheticmagnesia silica gel. The filter cake is washed with acetone and thefiltrate is concentrated under reduced pressure to give 40 g. of darkgum. The gum (20 g.) is chromatographed on a column of 300 g. of silicagel using chloroformzethanol (99.3:0.7) as eluting solvent and 250 ml.cuts are collected. Evaporation of cuts 5-11 gives the product as aglass. The combined glass from two column purifications is crystallizedfrom methanol to give 6.95 g. of methyl 17 u[(methylthio)methoxy1yohimban-16acarboxylate as tan crystals, M.P. 195198 C. Recrystallization of 2.0 g. from 20 ml. of methanol gives 1.2 g.of olf white crystals, M.P. 198200 C.

Other compounds which can be prepared according to the above-describedprocedure are, for example:

methyl 3-epi 17fi-[(methylthio)methoxy]yohimban-l6acarboxylate, and

methyl 3-epi 17a-[(methylthio)methoxyjlyohirrrban-l6ucarboxylate.

Example 2 PREPARATION OF METHYL 17-fl-[(METHYLTHDO)-METHOXY]YOHIMBAN-lGa-CARBOXYLATE A mixture of 18.0 g. of fl-yohimbine,ml. of dimethyl sulfoxide and 100 ml. of acetic anhydride is allowed tostand at room temperature for 18 hours. The mixture is poured onto 400g. of ice, allowed to stand one-half hour, and the chilled mixture ismade basic with concentrated ammonium hydroxide. After standing 1.5hours the chilled mixture is filtered and the solid is washed with waterto give 18.5 g. of the product. Chromatography of 9.0 g. of this producton 300 g. of silica gel with chloroformzethanol (99320.7) (200 ml. cuts)affords, after evaporation of the eluates, methyl 17,5-[(methylthio)methoxy]yohimban 16cc carboxylate in fractions 1318.Crystallization from methanol gives 1.0 g. of product as ofl? whitecrystals, M.P. 188l90 C.

Other compounds which can be prepared according to the above-describedprocedure are, for example:

methyl 17c: [(methylthio)rnethoxy]yohirnban-l8a-carboxylate, and methyl[(methylthio)methoxy1yohirnban-18a-carboxylate.

Example 3 PREPARATION OF METHYL 17a-[(METHYLTHIO)ME-THOXYIALLOYOHIMBANJGB-CARBOXYLATE A mixture of 2.12 g. of a-yohirnbine,25 ml. of dry dimethyl sulfoxide and 4.0 ml. of acetic anhydride isstirred at room temperature for 21 hours. The 'mixture is poured onto 60g. of ice and 10 ml. of water and made basic with concentrated ammoniumhydroxide. The solid which separates is removed by filtration and washedwith water. After drying overnight the solid is extracted into ether andthe'solution filtered through 10 g. of synthetic magnesia silica gel.The filter cake is washed with ether and the combined filtrates areconcentrated in vacuo to give 2.1 g. of a pale orange glass.Chromatography of 4.1 g. of this glass over 200 g. of silca gel withchloroforrmethanol (99520.5) as eluting solvent (100 ml. cuts) affords,after evaporation, methyl 17- (methylthio) methoxy] alloyohirnban-l6,8-carboxylate in fractions 9 and 10. Crystallization from methanolgives 0.48 g. of product as tan crystals, M.P.: sinters above 92 C. to aviscous mass which slowly changes to a liquid,

Other compounds which can be prepared according to the above-describedprocedure are, for example:

What is claimed is:

1. A 17-[(methylthio)methoxy]yohimbane compound selected from the groupconsisting of those of the formula:

OCHzSCHn wherein R is selected from the group consisting of hydrogen andlower 'carboalkoxy and R is selected from the group consisting ofhydrogen and lower carboalkoxy, with the proviso that R; and R cannot bethe same;

and the pharmaceutically acceptable acid-addition salts thereof.

2. A compound according to claim 1 of the normal yohimbane serieswherein R is a-carbomethoxy and R is hydrogen; said compound having thealpha configuration at the 17-position.

3. A compound according to claim 1 of the normal yohimbane serieswherein R is a-carbomethoxy and R is hydrogen; said compound having thebeta configuration at the 17-position.

4. A compound according to claim 1 of the alloyohimbane series wherein Ris fi-carbomethoxy and R is hydrogen; said compound having the alphaconfiguration at the 17-position.

5. A compound according to claim 1 of the pseudo yohimbane serieswherein R is wcarbomethoxy and R is hydrogen; said compound having thebeta configuration at the 17-position.

6. A compound according to claim 1 of the pseudo yohimbane serieswherein R is u-carbomethoxy and R is hydrogen; said compound having thealpha configuration at the 17-p0sition.

7. A compound according to claim 1 of the epialloyohimbane serieswherein R is fl-carbomethoxy and R is hydrogen; said compound having thealpha configuration at the 17-position.

8. A compound according to claim 1 of the alloyohimbane series wherein Ris ,B-carbomethoxy and R is hydrogen; said compound having the 'betaconfiguration at the 17-position.

9. A compound according to claim 1 of the normal yohimbane serieswherein R is hydrogen and R is acarbomethoxy; said compound having thealpha configuration at the 17-position.

10. A compound according to claim 1 of the normal yohimbane serieswherein R is hydrogen and R is u-carbomethoxy; said compound having thebeta configuration at the 17-position.

JAMES A. PA'ITEN, Primary Examiner.

